Stereoselective synthesis of versatile 2-chloromercurium-3,5-syn-dihydroxy esters via intramolecular oxymercuration

Article abstract of DOI:10.1016/j.tet.2008.06.094

Regio- and stereocontrolled alkoxy mercuration of α,β-unsaturated esters allows direct access to 1,3-syn diols in good yields. Demercuration of adducts leads to 1,3 skipped dihydroxy esters, alcohols, and α-halo esters. The deprotection of acetonide with Amberlyst 15 on 1,3-syn-dihydroxy esters gives the corresponding δ-lactones.

Full text of DOI:10.1016/j.tet.2008.06.094

Tetrahedron 64 (2008) 8766–8772
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of versatile 2-chloromercurium-3,5-syn-dihydroxy
esters via intramolecular oxymercuration
*
*
Carlo Bonini , Maria Campaniello, Lucia Chiummiento , Valeria Videtta
`
Dipartimento di Chimica, Universita degli Studi della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Regio- and stereocontrolled alkoxy mercuration of
diols in good yields. Demercuration of adducts leads to 1,3 skipped dihydroxy esters, alcohols, and
a
,
b
-unsaturated esters allows direct access to 1,3-syn
-halo
esters. The deprotection of acetonide with Amberlyst 15 on 1,3-syn-dihydroxy esters gives the corre-
sponding -lactones.
Received 24 January 2008
Received in revised form 11 June 2008
Accepted 26 June 2008
a
d
Available online 28 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Oxymercuration
1,3-syn-Diol
Demercuration
Lactonization
OH
1. Introduction
PO
PO
CO2Me
CO2Me
n
1
Many polyketide-derived natural products, containing syn or
anti-1,3-diol units, display a range of potent and different biological
properties, such as antibacterial and antifungal as well as cytotoxic
and immunosuppressive activities.1 Since no general approach
exists for the flexible synthesis of polyols and other polyketide-
derived structural units, a multitude of suitable and specific
methods for the stereoselective synthesis of 1,3-diols has been
developed.2
Our group has been engaged in the development of practical
synthetic approaches toward chiral syn- and anti-1,3-diol,3 and in
their application to the syntheses of natural macrolides.4
Inspired by work on the diastereoselective oxymercurations of
allylic and homoallylic alcohols5 and by chirality transfer6 we were
interested in performing an intramolecular oxymercuration on
O
n
O
*
*
*
2
reductive
demercuration
HgX
O
n
O
PO
CO2Me
*
*
O
n
O
*
PO
CO2Me
CO2Me
*
*
X
O
O
Hg-halogen
exchange
PO
*
*
n
*
R'
alkylation
Scheme 1.
d-hydroxy a,b-unsaturated methyl esters of type 1 shown in
Scheme 1. Herein we report the synthesis of a 1,3-diol array by
introducing the first chiral center as a secondary alcohol. Particu-
larly useful in this sense is its hemiketal derivative, which could
direct the addition to neighboring carbon–carbon double bonds. In
several cases this process results in a highly selective conversion of
an unsaturated alcohol into a single diol product.
A substrate of type 1 could directly produce two new stereo-
centers, affording the 3,5 dihydroxy ketal 2. So the 1,3-diol ester 2
could be seen as an important precursor for different trans-
formations of functional groups.
Moreover,
a
-mercurio esters, derived from the regiospecific
-unsaturated esters, have been
process of oxymercuration of
a,b
studied for some time,7 but have received very limited attention
over more recent years. Normally, intramolecular oxymercurations
are performed on terminal olefins, on electron-rich systems or
cyclic compounds and there are no examples about nucleophilic
hemiketal or hemiacetal additions on
This electrophile-mediated addition affords vicinal functionalised
a,b-unsaturated systems.
* Corresponding authors. Tel.: þ39 0971 202255; fax: þ39 0971 202223.
E-mail address: lucia.chiummiento@unibas.it (C. Bonini).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.094

C. Bonini et al. / Tetrahedron 64 (2008) 8766–8772
8767
Table 1
products to be further easily transformed. In fact, the weak C–Hg
bonds can readily enter into metal-exchange reactions with palla-
dium reagents, or halogen replacement, and atom-transfer
reactions.8,9
Entry
P
n
Substratea
Product 5 yield [%]
Product 1 E/Z ratiob
yield [%]
OH
BnO
1
Bn
1
3a
1a [94]
1b [84]
1c [92]
1d [89]
>99:1
99:1
2. Results and discussion
5a [100]
OH
Searching for a straightforward preparation of the starting d-
PMBO
2
3
4
5
PMB
Bn
1
2
3
3b
4a
4b
hydroxy enoate synthons 1, we need to prepare the starting
homoallylic alcohols 5a–f (Scheme 2). These compounds were
easily prepared by two different routes in racemic form;10 (1) via
epoxide ring opening with vinylmagnesium bromide11 and (2) via
addition of allylmagnesium bromide to the corresponding
aldehydes.
5b [100]
OH
>99:1
>99:1
BnO
5c [83]
The final cross-metathesis reaction12 with methyl acrylate in the
presence of Grubbs(II) catalyst in CH2Cl2 at reflux for 3 h, smoothly
afforded the desired products 1a–f (Table 1).
Compounds 1, with variable chain lengths and different primary
hydroxyl protecting groups, were obtained in good overall yields
(84–96%) up to >99:1 E/Z ratio, except compound 1f, which was
obtained in 66% yield.
OH
BnO
Bn
5d [78]
OH
OH
Bn
4
4
4c
1e [96]
1f [66]
>99:1
BnO
5e [80]
5f [80]
Initially the oxymercuration reaction of 1a–f was performed
with Hg(OA)2 (1.1 equiv), followed by treatment with aq NaCl
(method A) but, after purification of the crude reaction mixture, we
did not obtain good results, as reported in Table 2. Low conversions
and yields were obtained with all substrates using method A. Better
yields were obtained using HgCl(OAc), method B,5b and in partic-
ular using HgCl(OAc) (2.5 equiv), Yb(OTf)3 (0.05 equiv) in acetone at
rt for 20–24 h (entries 10 and 11).13 Under these conditions 1a, 1c–e
were converted into acetonides 2a, 2c–e in high yields and isolated
as pure products in about 50% yield by column chromatography on
silica gel.14 When compounds 1b and 1f were treated according to
either method, the expected protected diols 2b,f were not formed,
but a large amount of by-products was detected (entries 2 and 6,
Table 2).
6
TBS
4d
99:1
TBSO
a
The glycidol 3a is commercially available, the aldehydes 4a–d were prepared by
oxidizing the corresponding commercial alcohols using PCC in CH2Cl2.
b
The E/Z ratio was determined by GC–MS analysis.
THF proceeded cleanly to afford a mixture of unstable epimers in
a 1:1 ratio at C2 9a,e in quantitative yields. Direct iodo acetalization
was first tested on compounds 1 without success, so this strategy
could represent a methodology for the direct insertion of halogen
atom
a to an ester moiety, as a useful chiral synthon for Refor-
matsky type reaction.20 Some attempts to perform the reaction in
a stereoselective fashion, by using molecular bromine in pyridine,
(reported with a total configuration retention)21 only generated the
two diastereomers in quantitative yield and in an 80:20 syn/anti
ratio.
It is noteworthy that only the 1,3-syn diol was found, as showed
by NMR spectroscopic analysis of the acetonides.15
As mentioned before, the obtained mercurial organic com-
pounds could be easily transformed. The reduction of the mercu-
rials 2a,e (Scheme 3) using standard conditions (NaBH4 in the
presence of aq sodium hydroxide in THF)16 afforded the desired
reduction product along with small amounts of the corresponding
carboxylic acids. Thus the demercurated esters 6a,e were isolated in
good yields (85–95%) when NaCNBH3 in acetone was used.17 The
facile hydrolysis of acetonides with Amberlyst 15 in MeOH18 di-
We have therefore showed that organomercurials could give
access to structurally diverse compounds through different re-
ductive conditions and halogenation reactions.
rectly afforded the corresponding
d-lactones 7a,e in high yields
3. Stereochemistry of oxymercuration
(80% and 86%), previously prepared and used as analogs of mevinic
acid3 as well of naturally occurring lactones.19
After several attempts, LiAlH4 in THF was found to be the re-
agent of choice for direct demercuration and reduction of the ester
group, affording 8a,e in 80–83% yield. Iodination of 2a,e with I2 in
We noticed that among the four possible diastereomers with the
relative stereochemistry of the two newly generated chiral centers
(1,2,4-syn/syn, syn/anti, anti/syn or anti/anti), only one compound
was isolated for each reaction.
O
PO
a
n
n = 1
OH
n
OH
n
O
3a,b
c
PO
PO
OMe
b
O
n=1- 4
n=1-4
5a-f
1a-f
PO
n = 2-4
H
n
4a-d
P = Bn, PMB, TBS,
Scheme 2. (a) Vinylmagnesium bromide, CuI, THF, ꢀ20 ꢁC, 20 min; (b) allylmagnesium bromide, THF, ꢀ20 ꢁC, 30 min; (c) methyl acrylate, Grubbs(II) catalyst, CH2Cl2, reflux, 3 h.

8768
C. Bonini et al. / Tetrahedron 64 (2008) 8766–8772
Table 2
Preparation of compounds 2a–f using Hg(OAc)2 or HgCl(OAc)
O
O
O
OH
O
Yb(OTf)3 (0.05 equiv), method A or B
R
OMe
R
OMe
acetone, rt
2a-f
1a-f
HgCl
method A: Hg(OAc)2, NaCl
method B: HgCl(OAc)
Entry
1
Substrate 1
Time (h)
A or B [equiv]
Product 2 [crude]a[pure]b
2a
OH
20
24
24
A [1.1]
B [1.1]
B [2.5]
[60] [22]
[80] [36]
[90] [49]
BnO
CO2Me
CO2Me
CO2Me
CO2Me
1a
OH
2b
[d]c[d]
[d]c[d]
PMBO
2
3
4
5
43
24
A [1.1]
B [1.1]
1b
2c
OH
20
24
24
A [1.1]
B [1.1]
B [2.5]
[62] [22]
[70] [40]
[92] [51]
BnO
1c
OH
2d
[65] [34]
[92] [53]
BnO
24
22
A [1.1]
B [2.5]
1d
2e
OH
24
20
22
A [1.1]
B [1.1]
B [2.5]
[65] [36]
[70] [43]
[91] [50]
CO2Me
CO2Me
BnO
1e
OH
2f
[d]c[d]
[d]c[d]
TBSO
6
20
20
A [1.1]
B [1.1]
1f
a
Yield of product 2 evaluated on the crude by 1H NMR spectroscopic analysis.
Yield of product 2 after column chromatography on silica gel.
Complete disappearance and degradation of the substrate.
b
c
The intramolecular addition on the pure trans-1 proceeded with
order to improve the conversion to a single diastereomer the re-
actions were left for 20 h, as reported in Table 2. Compounds 2 were
thus subjected to the equilibrating oxymercuration condition with
the thermodynamically more stable syn 1,3-diols to be the expected
predominant.5b
excellent selectivity when reactions were left for more than 12 h
and the 1,3-diol unit showed only the relative syn-configuration. In
the first period of the reaction, two acetonides were detected
showing both the syn- and anti-1,3-dihydroxy relationship.15 In
O
O
O
O
O
R
OH
R
OMe
8a,e
6a,e
c
a
b
O
O
O
R
OMe
O
HgCl
e
2a,e
d
O
R
OH
O
O
O
7a,e
R
OMe
mevinic acid
precursors
I
O
O
9a,e
1: 1 syn/anti
O
R
OMe
80: 20 syn/anti
Br
10a
Scheme 3. (a) NaBH3CN, acetone, 2 h, rt (6a, 95%; 6e 85%); (b) Amberlyst 15, MeOH, 18 h, reflux, (7a, 80%; 7e, 86%); (c) LiAlH4, THF, 3 h, rt (8a, 83%; 8e, 80%); (d) I2, THF, 2 h, rt (9a,
100%; 9e, 100%); (e) Br2, pyridine, ꢀ20 ꢁC, 1 h, (10a, 100%, syn/anti 80:20).

C. Bonini et al. / Tetrahedron 64 (2008) 8766–8772
8769
Yb
O-
Hg++
OMe
Yb
OH
-
O
O
O
BnO
O
O
Hg++
cis-1a
MeO
O
OMe
OBn
BnO
O
O
O
O
O
O
BnO
BnO
OMe
OMe
HgCl
HgCl
1,3-diol isomerization
O
O
O
O
O
O
BnO
BnO
OMe
OMe
HgCl
Scheme 4.
HgCl
2a
2a'
1: 1
By 1H NMR spectroscopic analysis we noticed that the syn 1,3-
diol 2a22 showed H-2 at 3.50 ppm as a doublet with 3J2,3 6.6 Hz and
H-3 at 4.65 ppm as a multiplet, without any useful information on
the C-2 relative configuration. Also the NOESY experiments on
product 2a did not allow the relative configuration of the C-2 car-
bon to be determined.23
presented in this communication should encourage the research for
alternative electrophiles to perform these transformations.
5. Experimental section
5.1. General remarks
Therefore in order to obtain more information, pure cis isomer
ester 1a (Scheme 4) was reacted under the usual conditions. Sur-
prisingly, two diastereomers were isolated in all 50% yield with 1:1
ratio. Both products possess relative syn-configuration of the 1,3-
dihydroxy moiety (as confirmed by 13C NMR), but opposite con-
figuration on the stereocenter bearing the mercury atom, with
identical NMR spectroscopic data for 2a obtained from trans-1a.
The resonances for H-2 were at 3.50 ppm with 3J2,3 of 6.6 Hz for the
diastereomer 2a (the same obtained from the trans-1a) and
All chemicals were purchased from Aldrich or Fluka and were
used without further purification. Solvents were dried and distilled
by classical procedures. NMR spectra were recorded with Varian
400 and 500 and Bruker 300 spectrometers, operating at 300, 400,
and 500 MHz (1H) and 100 and 125 MHz (13C), respectively.
Chemical shifts (d) are reported in parts per million (ppm) relative
to CHCl3
(
d
¼7.27 ppm) for 1H NMR spectroscopy. For 13C NMR,
chemical shifts were reported in the scale relative to CHCl3
3
3.23 ppm with J2,3 of 7.5 Hz for the other diatereoisomer 2a0. As
(d¼77.0 ppm) as an internal reference. Multiplicities are abbrevi-
reported for methoxymercuriated diastereomers7b,7c the larger
ated as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad. The coupling constants are given in hertz (Hz). ESI-Tof mass
spectra were recorded for organomercuriated compounds with
a ToF micromass waters instrument using polyphosphoric acids as
internal standard, for the other compounds mass spectra
were obtained by GC/MS with electron impact ionization.
Column chromatography was performed using silica gel 60 (0.040–
0.063 mm). Thin-layer chromatography (TLC) was performed
using precoated plates of silica gel 60 F254 and visualized under
ultraviolet irradiation (254 nm) or by phosphomolybdic acid
solution.
3
value in J2,3 can be confidently assigned to the isomer with the
erythro-configuration, so now we tentatively assign to compound
2a the 1,2,4-syn/syn-configuration and to compound 2a0 the 1,2,4-
anti/syn-configuration.
A possible mechanism for the formation of the two dia-
stereomers is shown in Scheme 4. By the coordination of the
mercury atom to the carbonyl oxygen24 the
a,b-unsaturated ester
cis-1a isomerizes in the reaction medium to the trans-1a. Both
compounds provide firstly the two 1,3-anti diols and subsequently,
as already reported,5b the more stable 1,3-syn diols, respectively,
compounds 2a and 2a0, the only detected and isolated.
5.2. Cross-metathesis reaction
4. Conclusions
5.2.1. General procedure
Compounds 5a–f25 (1 equiv) were dissolved in CH2Cl2 (0.1 M).
Methyl acrylates (3 equiv) and Grubbs(II) catalyst (0.01 equiv) were
added and the mixture was heated at reflux until completion of the
reaction (2–3 h, monitored by TLC). The mixture was concentrated
and the crudes 1a–f20 were purified by column chromatography on
silica gel (eluent: petroleum ether/EtOAc 7:3).
The diastereoselective nucleophilic addition to a,b-unsaturated
esters mediated by mercury(II) salts with concomitant chirality
transfer provides a useful strategy for the stereoselective elabora-
tion of acyclic structures bearing several contiguous stereocenters.
Moreover, the different demercuriation procedures led to a variety
of functionalities on the substrate making this sequence of re-
actions a versatile methodology in the preparation of 1,3-diol
subunits.
5.2.1.1. Methyl 9-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-non-2-
enoate (1f). Colorless liquid (130 mg, 66%). 1H NMR (500 MHz,
Although the use of mercury salts limits the development of
these reactions to academic research activities, the results
CDCl3):
d
¼7.04–7.00 (m, 1H), 5.92 (d, J¼18.0 Hz, 1H), 3.82–3.78 (m,
1H), 3.78 (s, 3H), 3.63 (t, J¼6.0 Hz, 2H), 2.52–2.38 (m, 2H), 1.75 (br s,

8770
C. Bonini et al. / Tetrahedron 64 (2008) 8766–8772
1H), 1.60–1.40 (m, 6H), 0.92 (s, 9H), 0.05 (s, 6H); 13C NMR (125 MHz,
5.3.1.5. {(1S
dioxan-4-yl]-2-methoxy-2-oxoethyl} mercury(II) chloride (2e). White
deliquescent solid (70 mg, 50%); 1H NMR (500 MHz, CDCl3):
*
)-1-[(4R
*
,6R
*
)-6-(4-(Benzyloxy)butyl)-2,2-dimethyl-1,3-
CDCl3):
d
¼167.0, 145.8, 123.7, 70.7, 63.3, 51.8, 40.5, 36.9, 32.7, 26.2,
22.2, 18.6, -5.0. IR (cmꢀ1): 2927, 1724, 1657, 1471. GC–MS (EI): m/z
(%)¼301 [Mꢀ15þ], 115 (100). Anal. Calcd for C16H32O4Si: C, 60.72; H,
10.19. Found: C, 60.69; H, 10.18.
d¼7.38–
7.33 (m, 5H), 4.62–4.57 (m, 1H), 4.48 (s, 2H), 3.89–3.80 (m, 1H), 3.70
(s, 3H), 3.48–3.44 (m, 3H), 2.10–2.07 (m, 1H), 1.62–1.00 (m, 7H), 1.48
(s, 3H),1.38 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼171.6, 138.5, 129.5,
128.3, 127.5, 99.1, 72.8, 70.1, 68.4, 68.3, 58.2, 52.0, 40.8, 35.9, 30.1,
29.5, 28.5, 21.6, 20.0. ESI-Tof MS calcd for C20H29ClHgO5 [Mþ] 586.14,
found [MꢀClþ] 551.36.
5.3. Oxymercuration reaction
5.3.1. General procedure
All organomercury compounds should be regarded as poten-
tially toxic and manipulated in a well-ventilated hood. Compounds
1a–f (1 equiv) were dissolved in freshly distilled acetone (0.1 M),
and in sequence HgCl(OAc) (1.1–2.5 equiv) and Yb(OTf)3
(0.05 equiv) were added. The mixture was stirred at rt for 20–24 h.
The reaction was quenched by adding Et3N (1 equiv) and then the
mixture was concentrated. The crude mixture was diluted with
ethyl acetate and washed with brine. The organic layer was dried
over anhydrous Na2SO4, filtered, and concentrated. The reaction
mixture was purified on silica gel chromatography affording pure
products 2a–e (eluent: petroleum ether/EtOAc 4:3) as colorless oil
or white solid.
5.4. Reduction with NaCNBH3
5.4.1. General procedure
To a solution of 2a,e (1 equiv) in freshly distilled acetone
(0.05 M) NaCNBH3 (1 equiv) was added. Immediately the pre-
cipitated mercury was filtered off through Celite washing with
acetone. The crude mixture was concentrated and purified by col-
umn chromatography on silica gel (eluent: petroleum ether/EtOAc
7:3) to afford pure products 6a,e as oils.
5.4.1.1. Methyl {(4R
dioxan-4-yl}-acetate (6a). Brown oil (459 mg, 95%). 1H NMR
(400 MHz, CDCl3):
*
,6S )-6-[(benzyloxy)methyl]-2,2-dimethyl-1,3-
*
d
¼7.28–7.19 (m, 5H), 4.52 (d, J¼12.0 Hz,1H), 4.46
5.3.1.1. {(1S
*
)-1-[(4R
*
,6S
*
)-6-((Benzyloxy)methyl)-2,2-dimethyl-1,3-
(d, J¼12.0 Hz, 1H), 4.28–4.25 (m, 1H), 4.07–4.03 (m, 1H), 3.61 (s,
3H), 3.43 (dd, J¼10.0, 5.6 Hz, 1H), 3.31(dd, J¼10.0, 4.8 Hz, 1H), 2.49
(dd, J¼15.2, 6.8 Hz, 1H), 2.32 (dd, J¼15.2, 6.0 Hz, 1H), 1.56–1.53 (m,
1H), 1.41 (s, 3H), 1.33 (s, 3H), 1.23–1.14 (m, 1H); 13C NMR (100 MHz,
dioxan-4-yl]-2-methoxy-2-oxoethyl} mercury(II) chloride (2a). White
solid (200 mg, 49%); mp: 100–102 ꢁC; 1H NMR (500 MHz, CDCl3):
d
¼7.40–7.25 (m, 5H), 4.63–4.56 (m, 1H), 4.60 (d, J¼12 Hz, 1H), 4.55
(d, J¼12 Hz, 1H), 4.18–4.12 (m, 1H), 3.70 (s, 3H), 3.52–3.49 (m, 1H),
3.52 (d, J¼6.6 Hz, 1H), 3.40 (dd, J¼10.0, 4.4 Hz, 1H), 2.08 (dt, J¼14.0,
3 Hz, 1H), 1.47 (s, 3H), 1.39 (s, 3H), 1.28–1.13 (m, 1H); 13C NMR
CDCl3):
d
¼171.3, 138.1, 128.4, 127.7, 127.6, 98.9, 73.4, 73.4, 68.3, 65.6,
51.7, 41.2, 33.2, 30.0, 29.9, 19.6. IR (neat, KBr): 2997, 2957, 2897,
2364, 1735, 1654, 1278, 1120 cmꢀ1. GC–MS (EI): m/z (%)¼293
[Mꢀ15þ], 91 (100). Anal. Calcd for C17H24O5: C, 66.21; H, 7.84.
Found: C, 66.29; H, 7.89.
(125 MHz, CDCl3):
d
¼171.5, 137.9, 128.4, 127.8, 127.7, 99.3, 73.5, 73.1,
68.1, 67.9, 58.1, 52.0, 37.3, 30.0, 20.0. IR (neat, KBr): 2998, 2951, 2940,
2886, 1719, 1700, 1263, 1204, 1198, 1129, 1102 cmꢀ1. ESI-Tof MS calcd
for C17H23ClHgO5 [Mþ] 544.09, found [MꢀClþ] 509.36.
5.4.1.2. Methyl {(4R
dioxan-4-yl}-acetate (6e). Brown oil (45 mg, 85%). 1H NMR
(500 MHz, CDCl3):
*
,6R )-6-(4-(benzyloxy)butyl)-2,2-dimethyl-1,3-
*
5.3.1.2. {(1R
dioxan-4-yl]-2-methoxy-2-oxoethyl} mercury(II) chloride (2a0). Thick
colorless oil (20 mg, 25%); 1H NMR (500 MHz, CDCl3):
*
)-1-[(4R
*
,6S
*
)-6-((Benzyloxy)methyl)-2,2-dimethyl-1,3-
d
¼7.36–7.32 (m, 5H), 4.51 (s, 2H), 4.32–4.28 (m,
1H), 3.87–3.83 (m, 1H), 3.70 (s, 3H), 3.48 (t, J¼5.8 Hz, 2H), 2.56 (dd,
d¼7.40–7.25
J¼15.5, 6.8, 2H), 2.38 (dd, J¼15.5, 6.2 Hz, 2H), 1.61–1.10 (m, 8H), 1.45
(m, 5H), 4.62–4.54 (m, 3H), 4.14–4.10 (m, 1H), 3.70 (s, 3H), 3.53–4.48
(m, 1H), 3.42–3.38 (m, 1H), 3.28–3.23 (m, 1H), 1.73 (br d, J¼13.0 Hz,
1H), 1.51 (s, 3H), 1.41 (s, 3H), 1.23–1.15 (m, 1H); 13C NMR (125 MHz,
(s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3):
d
¼171.5, 138.5, 128.3,
127.6, 127.5, 98.7, 72.8, 70.2, 68.6, 65.9, 51.6, 41.2, 36.4, 36.0, 30.0,
29.6, 21.5, 19.7. IR (neat, KBr): 2996, 2953, 2897, 2364, 1735,
1654, 1278, 1120, 1097 cmꢀ1. GC–MS (EI): m/z (%)¼335 [Mꢀ15þ], 91
(100). Anal. Calcd for C20H30O5: C, 68.54; H, 8.63. Found: C, 68.59; H,
8.68.
CDCl3):
d
¼171.9, 138.0, 128.5, 127.7, 127.7, 99.5, 73.4, 73.3, 73.0, 68.2,
57.9, 52.0, 34.8, 30.1, 20.0. IR (neat, KBr): 2998, 2951, 2940, 2886,
1719, 1700, 1263, 1204, 1198, 1129, 1102 cmꢀ1. ESI-Tof MS calcd for
C17H23ClHgO5 [Mþ] 544.09, found [MꢀClþ] 509.36.
5.5. Lactonization
5.3.1.3. {(1S
dioxan-4-yl]-2-methoxy-2-oxoethyl} mercury(II) chloride (2c). Thick
colorless oil (74 mg, 51%); 1H NMR (500 MHz, CDCl3):
*
)-1-[(4R
*
,6R
*
)-6-(2-(Benzyloxy)ethyl)-2,2-dimethyl-1,3-
5.5.1. General procedure
d
¼7.39–7.30
To a solution of 6a,e (1 equiv) in dry MeOH (0.1 M), Amberlyst 15
(200 mg/mmol) was added. The mixture was stirred at reflux
temperature overnight. The reaction was quenched by filtering
with ethyl acetate and concentrated. The residue was purified by
column chromatography on silica gel (eluent: petroleum ether/
EtOAc 95:5) to afford pure products 7a,e as white solids.
(m, 5H), 4.65–4.63 (m, 1H), 4.54 (d, J¼12.0 Hz, 1H), 4.51 (d,
J¼12.0 Hz, 1H), 4.17–4.15 (m, 1H), 3.71 (s, 3H), 3.62–3.58 (m, 1H),
3.58–3.54 (m, 2H), 2.20 (br d, J¼12.5 Hz, 1H), 1.80–1.76 (m, 2H), 1.46
(s, 3H), 1.37 (s, 3H), 1.18–1.14 (m, 1H); 13C NMR (125 MHz, CDCl3):
d
¼171.5, 145.5, 138.4, 128.5, 127.8, 99.2, 73.0, 68.2, 65.9, 65.6, 58.2,
52.0, 40.9, 36.3, 30.1, 20.1. ESI-Tof MS calcd for C18H25ClHgO5 [Mþ]
558.11, found [MꢀClþ] 523.34.
5.5.1.1. (4R
*
,6S )-6-[(Benzyloxy)methyl]-tetrahydro-4-hydroxypyran-
*
2-one (7a). Same spectroscopic data reported in the literature.19a
5.3.1.4. {(1S
dioxan-4-yl]-2-methoxy-2-oxoethyl} mercury(II) chloride (2d). Thick
colorless oil (92 mg, 53%); 1H NMR (300 MHz, CDCl3):
*
)-1-[(4R
*
,6R )-6-(3-(Benzyloxy)propyl)-2,2-dimethyl-1,3-
*
5.5.1.2. (4S
2-one (7e). White solid (56 mg, 86%), dec: 120 ꢁC. 1H NMR
(500 MHz, CDCl3):
*
,6S
*
)-6-[4-(Benzyloxy)butyl]-tetrahydro-4-hydroxypyran-
d¼7.38–7.34
(m, 5H), 4.58–4.54 (m, 1H), 4.52 (s, 2H), 3.90–3.84 (m, 1H), 3.71 (s,
3H), 3.52–3.48 (m, H), 2.20 (br d, J¼12.0 Hz, 1H), 1.64–1.58 (m, 4H),
1.44 (s, 3H), 1.38 (s, 3H), 1.08–0.82 (m, 1H); 13C NMR (125 MHz,
d¼7.35–7.27 (m, 5H), 4.78–4.64 (m, 1H), 4.51 (s,
2H), 4.34–4.32 (m, 1H), 3.49 (t, J¼6.0 Hz, 2H), 2.69 (dd, J¼17.5,
5.0 Hz, 1H), 2.62 (dd, J¼17.5, 3.5 Hz, 1H), 1.94 (d, J¼12.5 Hz, 1H),
CDCl3):
d
¼171.5, 138.5, 128.4, 127.8, 127.5, 99.1, 72.8, 69.9, 68.2, 65.6,
1.78–1.50 (m, 7H); 13C NMR (125 MHz, CDCl3):
d¼170.2, 138.5,
58.2, 52.0, 40.8, 32.7, 30.1, 25.2, 20.1. ESI-Tof MS calcd for
129.5, 128.5, 127.6, 75.7, 73.0, 70.0, 62.8, 38.6, 36.0, 35.2, 29.5, 21.6.
IR (neat, KBr): 2948, 2908, 2365, 2352, 1735, 1235, 1097 cmꢀ1. GC–
C
19H27ClHgO5 [Mþ] 572.13, found [MꢀClþ] 537.34.

C. Bonini et al. / Tetrahedron 64 (2008) 8766–8772
8771
MS (EI): m/z (%)¼259 [Mꢀ18þ], 91 (100). Anal. Calcd for C16H22O4:
5.8. Bromination
C, 69.04; H, 7.97. Found: C, 69.09; H, 7.95.
5.8.1. Methyl 2-{(4R
*
,6S )-6-[(benzyloxy)methyl]-2,2-dimethyl-
*
1,3-dioxan-4-yl}-2-bromoacetate (10a)
5.6. Reduction with LiAlH4
To a solution of 2a (1 equiv) in dry pyridine (0.1 M) was added
Br2 (1 equiv). The reaction mixture was stirred at ꢀ20 ꢁC for 1 h.
At complete disappearance of the substrate, the reaction mixture
was filtered and concentrated under vacuum to afford product 9a
as red oil in quantitative yield (80 mg) and in 80:20 dia-
stereomeric ratio syn/anti. 1H NMR (500 MHz, CDCl3) of the major
5.6.1. General procedure
To a solution of 2a,e (1 equiv) in dry THF (0.1 M) LiAlH4
(4 equiv) was added. The mixture was stirred at rt for 18–24 h
until disappearance of the substrate. The reaction was quenched
adding ethyl acetate and a saturated solution of aq NH4Cl. The
mixture was stirred for several hours. The organic layer was
separated, dried over Na2SO4, filtered, and concentrated. The
residue was purified by column chromatography on silica gel
(eluent: petroleum ether/EtOAc 1:1) to afford pure products 8a,e
as colorless oils.
diastereomer:
d
¼7.38–7.32 (m, 5H), 4.62–4.55 (m, 2H), 4.30–4.26
(m, 1H), 4.13–4.11 (m, 1H), 3.98 (d, J¼9.0 Hz, 1H), 3.79 (s, 3H),
3.54–3.51 (m, 1H), 3.44–3.41 (m, 1H), 2.00 (br d, J¼12.5 Hz, 1H),
1.48 (s, 3H), 1.44 (s, 3H), 1.25–1.21 (m, 1H). GC–MS (EI): m/z
(%)¼294 (100). Anal. Calcd for C17H23BrO5: C, 52.72; H, 5.99.
Found: C, 52.69; H, 5.88.
5.6.1.1. 2-{(4S
4-yl}-ethanol (8a). Colorless oil (256 mg, 83%); 1H NMR (400 MHz,
CDCl3):
*
,6S
*
)-6-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxan-
Acknowledgements
d
¼7.38–7.34 (m, 5H), 4.52 (d, J¼12.5 Hz, 1H), 4.48 (d,
Thanks are due to the MIUR for financial support. M.C. thanks
the USB for a grant.
J¼12.5 Hz, 1H), 4.10–4.02 (m, 2H), 3.72–3.68 (m, 2H), 3.46–3.42 (m,
1H), 3.33–3.29 (m, 1H), 2.40 (br s, 1H), 1.69–1.65 (m, 2H), 1.41 (s,
3H), 1.34 (s, 3H) 1.47–1.26 (m, 2H); 13C NMR (100 MHz, CDCl3):
References and notes
d
¼138.1, 128.4, 127.7, 127.6, 98.7, 73.4, 69.1, 68.4, 60.9, 38.1, 33.5,
30.1, 19.8. IR (neat, KBr): 3414, 2964, 2920, 2856, 1453, 1377, 1255,
1165, 1090, 1044 cmꢀ1. GC–MS (EI): m/z (%)¼281 [Mþ1þ], 91 (100).
Anal. Calcd for C16H24O4: C, 68.54; H, 8.63. Found: C, 68.56; H, 8.60.
1. Nakata, T. In Macrolide Antibiotics. Chemistry, Biology, and Practice, 2nd ed.;
Omura, S., Ed.; Academic Press: San Diego, 2002; pp 181–284.
2. (a) Schenider, C. Angew. Chem., Int. Ed. 1998, 37, 1375–1378; (b) Hoffmann, R. W.
Angew. Chem., Int. Ed. 2003, 42, 1096–1109; (c) Bode, S. E.; Wolberg, M.; Muller,
M. Synthesis 2006, 557–588.
3. (a) Bonini, C.; Racioppi, R.; Righi, G.; Viggiani, L. J. Org. Chem. 1993, 58, 802–803;
(b) Bonini, C.; Chiummiento, L.; Funicello, M. Tetrahedron: Asymmetry 2001, 12,
2755–2760.
5.6.1.2. 2-{(4S
4-yl}-ethanol (8e). Colorless oil (63 mg, 80%). 1H NMR (300 MHz,
CDCl3):
¼7.36–7.27 (m, 5H), 4.51 (s, 2H), 4.13–4.09 (m, 1H), 3.84–
3.76 (m, 3H), 3.49 (t, J¼6.4 Hz, 2H), 1.78–1.21 (m, 10H), 1.46 (s, 3H),
1.40 (s, 3H); 13C NMR (75 MHz, CDCl3):
98.6, 72.9, 70.2, 69.6, 68.9, 61.1, 38.0, 36.5, 30.2, 29.7, 21.7, 19.9. IR
(neat, KBr): 3410, 2969, 2928, 2852, 1453, 1377, 1255, 1165, 1090,
1044 cmꢀ1. GC–MS (EI): m/z (%)¼307 [Mꢀ15þ], 91 (100). Anal. Calcd
for C19H30O4: C, 70.77; H, 9.38. Found: C, 70.74; H, 9.35.
*
*
,6R )-6-[4-(Benzyloxy)butyl]-2,2-dimethyl-1,3-dioxan-
d
4. (a) Bonini, C.; Chiummiento, L.; Martuscelli, A.; Viggiani, L. Tetrahedron Lett.
2004, 95, 2177–2179; (b) Bonini, B.; Chiummiento, L.; Pullez, M.; Solladie´, G.;
Colobert, F. J. Org. Chem. 2004, 69, 5015–5022.
d¼138.6, 128.7, 127.8, 127.6,
5. (a) Overman, L. E.; Campbell, C. B. J. Org. Chem. 1974, 39, 1474–1481; (b) Dreher,
S. D.; Hornberger, K. R.; Sarraf, S. T.; Leighton, J. L. Org. Lett. 2000, 2, 3197–3199.
6. (a) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446–2453; (b)
Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10899–10905; (c)
Wiseman, J. M.; McDonald, F.; Liotta, D. C. Org. Lett. 2005, 7, 3155–3157.
7. (a) Bloodworth, A. J.; Bunce, R. J. J. Chem. Soc. C 1971, 1453–1458; (b) Blood-
worth, A. J.; Griffin, I. M. J. Chem. Soc., Perkin Trans. 1 1974, 688–695; (c)
Cabaleiro, M. C.; Ayala, A. D.; Johnson, M. D. J. Chem. Soc., Perkin Trans. 2 1973,
1207–1212; (d) Gouzoules, F. H.; Whitney, R. A. J. Org. Chem.1986, 51, 2024–2030.
8. (a) Larock, R. C. Solvomercuration/Demercuration in Organic Synthesis; Springer:
Berlin, 1986; (b) Barluenga, J.; Yus, M. Chem. Rev. 1988, 88, 487–509.
9. (a) Kocovsky, P.; Dunn, V.; Gogoll, A.; Langer, V. J. Org. Chem. 1999, 64, 101–119;
(b) Russell, G. A.; Kulkarni, S. V. J. Org. Chem. 1993, 58, 2678–2685; (c) Raghavan,
S.; Tony, K. A.; Reddy, S. R. Tetrahedron Lett. 2001, 42, 8383–8386; (d) Lukkarila,
J. L.; Hamer, G. K.; Georges, M. K. Tetrahedron Lett. 2004, 45, 5317–5319.
10. We have prepared racemic compounds 5, but several methodologies could be
used to obtain optically pure compounds.
5.7. Iodination
5.7.1. General procedure
To a solution of 2a,e (1 equiv) in dry THF (0.1 M) was added I2
(1 equiv). The reaction mixture was stirred at rt for 4 h. At complete
disappearance of the substrate, the reaction was quenched by
adding a saturated aq solution of Na2S2O3. This mixture was
extracted with ethyl acetate. The organic layer was dried over
Na2SO4 and concentrated under vacuum to afford pure products
9a,e as red oils.
11. Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullez, M.; Colobert, F.; Solladie´, G.
Tetrahedron Lett. 2003, 44, 2695–2697.
12. (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–
4527; (b) De Weghe, P. V.; Eustache, J.; Cossy, J. Curr. Top. Med. Chem. 2005, 5,
1461–1472; (c) Schmidt, B.; Hermanns, J. Top. Organomet. Chem. 2004, 13, 223–
267; (d) Fu¨ rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043; (e) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
5.7.1.1. Methyl 2-{(4R
dioxan-4-yl}-2-iodoacetate (9a). Red oil (57 mg, 100%); mixture 1:1
of diastereomers: 1H NMR (400 MHz, CDCl3):
4.64–4.53 (m, 4H), 4.21–4.06 (m, 6H), 3.77 (s, 6H), 3.56–3.49 (m,
2H), 3.45–3.38 (m, 2H), 2.10 (dt, J¼12.8, 2.4 Hz, 1H), 1.76 (dt, J¼12.4,
2.4 Hz, 1H), 1.48 (s, 3H), 1.45 (s, 3H), 1.44 (s, 3H) 1.39 (s, 3H), 1.30–
110 (m, 2H). GC–MS (EI): m/z (%)¼419 [Mꢀ15þ], 91 (100). Anal.
Calcd for C17H23IO5: C, 47.02; H, 5.34. Found: C, 47.09; H, 5.38.
*
,6S )-6-[(benzyloxy)methyl]-2,2-dimethyl-1,3-
*
13. It is worth noting that the reaction did not occur when Hg(OTf)2 was used.
14. The lower yields reported for the isolated pure organomercurium(II) chloride
can be attributed to a difficult removal of the mercurium(II) salt. Moreover,
during column chromatography deprotected products from acetonide were
isolated, even if silica gel was deactivated using Et3N (5% v/v) in the eluent prior
to chromatography.
d¼7.35–7.32 (m, 10H),
15. The relative configuration syn or anti of the 1,3-diol was proved by the 1H
and 13C NMR analysis of the chemical shift of (CH3)2C in the corresponding
acetonides. Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511–
3515.
5.7.1.2. Methyl
1,3-dioxan-4-yl}-2-iodoacetate (9e). Red oil (45 mg, 100%); mixture
1:1 of diastereomers: 1H NMR (300 MHz, CDCl3):
10H), 4.64–4.53 (m, 4H), 4.28–4.24 (m, 6H), 3.72 (s, 6H), 3.50 (t,
J¼6.5 Hz, 4H), 1.30–110 (m, 2H) 2.11–2.09 (m, 1H), 1.80–0.84 (m,
15H), 1.40 (s, 3H), 1.38 (s, 3H), 1.32 (s, 3H), 1.24 (s, 3H). GC–MS (EI):
m/z (%)¼461 [Mꢀ15þ], 91 (100). Anal. Calcd for C20H29IO5: C, 50.43;
H, 6.14. Found: C, 50.49; H, 6.18.
2-{(4R
*
,6R )-6-[4-(benzyloxy)butyl]-2,2-dimethyl-
*
16. (a) Brown, H. C.; Geoghegan, P. J., Jr. J. Org. Chem. 1970, 35, 1844–1850; (b)
Griffith, R. C.; Gentile, R. J.; Davidson, T. A.; Scott, F. L. J. Org. Chem. 1979, 44,
3580–3583.
17. Thanavaro, A.; Spilling, C. D. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177,
1583–1586.
18. The unique example of deprotection of acetonide is reported for 1,2-diol in:
Batovska, D. I.; Kishimoto, T.; Bankova, V. S.; Kamenarska, Z. G.; Ubukata, M.
Molecules 2005, 10, 552–558.
19. (a) Guo, Z.; Chen, Y.; Goswami, A.; Hanson, R. L.; Patel, R. N. Tetrahedron:
Asymmetry 2006, 17, 1589–1602; (b) Aggarwal, V. K.; Bae, I.; Lee, H.-Y.
d¼7.35–7.32 (m,

8772
C. Bonini et al. / Tetrahedron 64 (2008) 8766–8772
Tetrahedron 2004, 60, 9725–9733; (c) Lautens, M.; Ma, S.; Yee, A. Tetrahedron
23. In order to transform the organomercurial compound 2a into the corre-
Lett. 1995, 24, 4185–4188; (d) Takano, S.; Sugihara, Y.; Ogasawara, K. Tetrahe-
dron: Asymmetry 1993, 4, 1795–1798; (e) Bonini, C.; Pucci, P.; Racioppi, R.;
Viggiani, L. Tetrahedron: Asymmetry 1992, 3, 29–32.
sponding structurally rigid lactone, hydrolyses of the ketal were made with 5%
HCl solution in THF and with AcOH in THF producing the starting
a,b-un-
saturated ester 5a. However, the acid condition led to product 5a during the
purification by column chromatography on silica gel of 2a.
20. (a) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210–1211; For a review, see:
(b) Babu, S. A.; Yasuda, M.; Shibata, I.; Baba, A. J. Org. Chem. 2005, 70, 10408–
10419 and references therein; (c) Babu, S. A.; Yasuda, M.; Okabe, Y.; Shibata, I.;
Baba, A. Org. Lett. 2006, 8, 3029–3032.
21. Nixon, J. R.; Cudd, M. A.; Porter, N. A. J. Org. Chem. 1978, 43, 4048–4052.
22. Because compound 2a showed definite signals in 1H NMR spectra, bidimen-
sional analyses (COSY, ghsqc) were made on it.
24. (a) Paquette, L. A.; Bolin, D. G.; Stepanian, M.; Branan, B. M.; Mallavadhani,
U. V.; Tae, J.; Eisenberg, S. W. E.; Rogers, R. D. J. Am. Chem. Soc. 1998, 120,
11603–11615; (b) Piccinini, P.; Vidari, G.; Zanoni, G. J. Am. Chem. Soc. 2004, 126,
5088–5089.
25. Compounds 5a–f and 1a–e are known products and they showed the same
spectroscopic characteristics reported in the literature.